Synthesis of Sulfapyridine metabolites

Petr Knesl , and Ulrich Jordis

Institute of Applied Synthetic Chemistry, Vienna University of Technology

Getreidemarkt 9, 1060 Vienna, Austria, [email protected]

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Abstract: 

Sulfapyridine (SP) is an antibacterial compound that is used as such and also the active metabolite of sulfosalzazine (SASP)  which shows antiphlogistic, antibacterial and immuno­modulatoric properties. Sulfapyridine is also used to help control dermatitis herpetiformis (Duhring's disease), a skin problem. It has been reported, that sulfapyridine is metabolized to 5-hydroxysulfapyridine  but no synthesis of this proposed metabolite has been published.We will report on the synthesis of thia and other potential metabolites of sulfapyridine.

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Introduction

Sulfapyridine (SP) and sulfasalazine (SASP) are used for the treatment of Crohn`s disease, rheumatoid arthritis and ulcer­ative colitis. When SASP is given orally it is partly absorbed unchanged and partly cleaved to aminosalicilic acid (5-ASA) and SP by bacterial azo reductase¹. SP is the therapeutically active moiety of SASP and undergoes further acetylation, hydroxylation and subsequent glucoronidation^2,3. The main metabolites were reported to be the N-acetyl­sulfapyridin (Ac-SP) and 5-hydroxy-sulfapyridine (OH-SP). Formation of Ac-SP and OH-SP are under genetic control and the proportion of acetylated and hydroxylated SP in serum and urine depends on the genetically determined acetylation and hydroxylation phenotypes of the patients⁴

The main meta­bolic pathway is depicted in Scheme 1.  

Scheme 1: Metabolism of SASP

Results and Discussion

To the best of our knowledge no references describing the synthesis of SASP metabolites have been reported, although several papers regarding analytical separation^4,5 and metabolism^1,2,3  including OH-SP and Ac-OH-SP were pub­lished. As  starting material for our synthesis we used 6-(4-nitro-phenylazo)-pyridin-3-ol⁶ 1 which was reduced with H₂/Pd to the higly unstable 5-hydroxy-2-aminopyridin 2 and imme­diately treated with N-Acetyl-sulfonylchlorid 3 to give a mixture of at least four products that were separated by LC (Scheme 2). From the isomers 4 and 5 the acetylated compounds 6 and 7 were prepared and the structures of 6 and 7 assigned by NMR thus allowing also to distinguish between 4 and 5.

Scheme 2: Synthesis of AC-OH-SP (4)

As none of these compounds showed LC/MS behavior similar to the expected metabolites in the urine of persons treated with SP, two additional known^7,8 oxygenated SP derivatives N-[4-(1-Oxy-pyridin-2-yl­sulfa­moyl)-phenyl]-acetamide 9 and N-[4-(Hydroxy-pyridin-2-yl-sulfamoyl)-phenyl]-acetamide 10   with the same mass as Ac-OH-SP were synthesized (Scheme 3). N-acetyl­sulfapyridine 8 was oxidized to afford a mixture of both products⁹ that were separated by LC. Neither 9 nor 10 could be detected in the urine of persons treated with SP.

Scheme 3: Synthesis of potential metabolites

Conclusion:

We have prepared and characterized potential SP metabolites. Preliminary results raise some doubts to the published metabolism of SP. The compounds await further biochemical investigation.

References:

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2.   Zheng, W.; Winter, S.M.; Mayersohn, M.; Bishop, J.B.; Sipes, I.G. Drug Metabolism and Disposition 21, 1993, 1091

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9.   Childress, S.J.; Scudi, J.V  J.Org.Chem.  23, 1958,  67